Science Editor

Two papers in the Feb. 1, 2008, issue of the Journal of Clinical Investigation reported new findings on myeloproliferative disease. One reported a new mechanism for the disorder to get started, and the other on how it progresses to outright acute myelogenous leukemia.

Myeloproliferative disorders are a group of slow-growing cancers, whose common denominator is that the bone marrow is overproducing one blood component or another. Though myeloproliferative disorders is something of an umbrella term, the different subgroups do share some frequent molecular abnormalities.

They also share the possibility of progressing to something more aggressive: Myeloproliferative disorders can progress to acute myelogenous leukemia or AML, and when they do, that's bad news for the affected patient.

In a paper titled "Constitutive activation of SHP2 in mice cooperates with ICSBP deficiency to accelerate progression to acute myeloid leukemia," researchers from Northwestern University and the Chicago Veteran's Health Administration Center reported new findings on what prompts the transition from myeloproliferative disorder to outright AML in mice lacking a leukemia tumor suppressor named interferon consensus sequence binding protein ICSBP.

Mice without ICSBP first develop myeloproliferative disorder, which progresses to AML over a period of months and kills 40 percent of them within a year. For the progression to occur, the cells have to sustain additional genetic damage on top of the loss of ICSBP. The authors wanted to identify the additional damage that is necessary for that progression to AML, since, as they write in their paper, "Identifying molecular markers of this transition may suggest targets for therapeutic intervention."

Because ICSBP, like many proteins, is regulated through its phosphorylation state, the researchers first generated ICSBP knockout cells, and added back in either normal ICSBP or a protein with a mutated tyrosine that tyrosine kinases would be unable to phosphorylate. They then performed bone marrow transplants with both types of cells. Mice whose bone marrow was reconstituted with wild-type protein did not develop AML, but roughly half of the animals who got the version that could not be phosphorylated had AML, as defined by the amount of undifferentiated cells in their blood, within 20 weeks.

Because AML, like most cancers, usually is the result of a series of genetic alterations, the researchers developed a cell lacking one copy of ICSBP together with an overactive phosphatase, which goes by the name of SHP2 and removes phosphate groups from proteins.

They found that a mutated SHP2 greatly accelerated the development of AML in mice with only one copy of ICSBP, suggesting that the interaction of the two proteins was important for the progression to AML. As they write in their paper, "these results are of potential clinical significance, because ICSBP deficiency and constitutive SHP2 activation may coexist in human myeloid malignancies."

Though they can manifest themselves in different ways, myeloproliferative diseases do share some frequent molecular abnormalities such as mutations in the tumor suppressor Dido and Jak kinase. A second paper in the same issue of JCI added another pathway whose malfunction results in myeloproliferation; that paper, too, focuses on protein phosphorylation.

In a paper titled "Regulation of myeloproliferation and M2 macrophage programming in mice by Lyn/Hck, SHIP, and Stat5," researchers from the La Jolla Institute for Allergy and Immunology and the University of California at San Francisco reported on another phosphorylation glitch that can cause a myeloproliferative disease characterized by overproduction of macrophages, which then infiltrate the lung, causing severe inflammation.

The authors studied two tyrosine kinases, Lyn and Hck, which belong to a family of kinases that regulates blood-forming cells. They found that double knockouts died by the age of 2 months and displayed several symptoms of myeloproliferative disease, which prompted the scientists to investigate the animals' blood-forming stem cells in greater detail. They found that the double knockouts had greater numbers of hematopoietic stem cells and myeloid progenitor cells, and that those cells produced greater numbers of macrophages than normal.

Additionally, the macrophages themselves were resistant to cell death, which led to an even greater surplus in their numbers. The effects of knocking out Lyn and Hck could be prevented by activating the phosphatase SHIP-1, which the authors ascribe to SHIP-1's inhibition of cytokines that stimulate blood stem cells to divide.